Process and intermediates for the preparation of aryl substituted pyrido[1,4]benzodiazepines

ABSTRACT

A process for preparing pyrido[1,4]benzodiazepines having antidepressant activity illustrated by the formula: ##STR1## wherein Ar is pyridinyl, thienyl or phenyl; R is alkali-metal ion, hydrogen, loweralkyl or an amine or an amine precursor on the end of a hydrocarbon chain and wherein in the process condensation of an amino-chloropyridine with an aryl(aminophenyl)methanone is accomplished with a strong non-nucleophilic base in stirrable admixture with an inert liquid carrier. Alternatively, condensation is accomplished sequentially using titanium tetrachloride first followed by non-nucleophilic base.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to a process for the preparation ofcertain known pyrido[1,4]benzodiazepines and novel chemicalintermediates therefor.

An important aspect of the process is the utilization of a strongnon-nucleophilic base such as sodium hydride to bring about condensationof an aminochloropyridine and an aryl(aminophenyl)methanone in admixturewith mobile inert liquid carrier to produce thepyrido[1,4]benzodiazepines. Alternatively, the condensation may bestarted with titanium tetrachloride and finished with thenon-nucleophilic base, in which case novel intermediates are producedand used.

2. Information Disclosure Statement

The aryl substituted pyrido[1,4]benzodiazepines prepared by the processof this invention are disclosed in S. African Pat. No. 81/7866 herebyincorporated by reference and are the subject of a correspondingcommonly assigned U.S. continuation application Ser. No. 395,218 filedJuly 6, 1982, now U.S. Pat. No. 4,447,361, hereby incorporated byreference. In the method of preparation disclosed in these references,amino-halo pyridines and aminoarylphenones are heated neat to givepyrido[1,4]benzodiazepines.

Commonly assigned U.S. application Ser. No. 431,997 filed Sept. 30,1982, now U.S. Pat. No. 4,480,100, describes preparation of[2-[(nitropyridinyl)amino]phenyl]arylmethanones, useful in preparationof the pyrido[1,4]benzodiazepines, by heating neat a halonitropyridinewith an aminoarylphenone.

Heating and reaction of such mixtures as described in the foregoingdisclosures involves difficult handling of viscous, sticky reactants andreaction products which adhere to the reaction vessel. In contrast, inthe present invention the diazepine ring is formed by a strongnon-nucleophilic base such as sodium hydride in a solvent or liquidcarrier which provides high mobility, ease of operation and increasedyields and direct formation of the sodium salts of the pyrido1,4-benzoidazepines.

Relating to the preparation of certain chemical intermediates used inthe process of the present invention, Yamamoto, M. and Yamamoto H. inChem. Pharm. Bull. 29(8), 2135-2156 (1981) describe the reaction of2-amino-4-chlorobenzophenone and an amine in the presence of titaniumtetrachloride as represented by the following equation: ##STR2## whereinR¹ =alkyl, cycloalkyl, phenylalkyl, dialkylaminoalkyl and4-morpholinoalkyl.

Also relating to preparation of certain other intermediates used in theprocess is a disclosure of phase-transfer catalyzed N-monoalkylation of2-aminobenzophenones of Mouzin, G., et al, in Synthesis CommunicationsGeorg. Thieme Verlag 1981, p. 448-449. as represented by the followingequation: ##STR3## wherein R=CH₃, --C₂ H₅ or allyl; X¹ =Cl or Br; X² =H,Cl or F.

SUMMARY OF THE INVENTION

Pyridobenzodiazepine compounds which are prepared directly by the novelprocess of the present invention have the formula: ##STR4## wherein R isselected from the group consisting of alkali-metal cation (M⁺),hydrogen, --alk¹ --Q wherein Q is selected from hydrogen, halo, --NR¹R², --N═CH--O--C₂ H₅ or ##STR5##

R¹ and R² are selected from the group consisting of loweralkyl,--C(O)O--loweralkyl or R¹ and R² taken together with the adjacentnitrogen atom may form a heterocyclic residue selected from the groupconsisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl,4-morpholinyl, 1-piperazinyl, and 4-substituted-piperazin-1-yl;

Ar is selected from the group consisting of 2, 3 and 4-pyridinyl, 2 or3-thienyl, phenyl or phenyl substituted by 1 to 3 radicals selected fromhalo, loweralkyl, loweralkoxy, trifluoromethyl or nitro and may be thesame or different;

alk¹ is a straight or branched hydrocarbon chain containing 1-8 carbonatoms;

Z is selected from the group consisting of hydrogen, halogen,loweralkyl, loweralkoxy, hydroxy or nitro;

Y is selected from the group consisting of hydrogen or 1-2 radicalsselected from loweralkyl, loweralkoxy or hydroxy and may be the same ordifferent, and the acid addition salts thereof except when R=M⁺.

The compounds of Formula I have utility as antidepressantpharmaceuticals or as intermediates in the preparation of othercompounds of Formula I and of Formula I_(p) described hereinbelow.

Additionally, the compounds of Formula I wherein R is ##STR6## have beenused to prepare compounds of Formula I wherein R is --alk¹ --R¹ R² vianovel intermediates wherein R is alk¹ --OH and alk¹ --OSO₂ W wherein Wis as defined hereinbelow.

In the further definition of symbols in the formulas hereon and wherethey appear elsewhere throughout this specification and claims, theterms have the following significance.

The "alk" straight or branched connecting hydrocarbon chain containing1-8 carbons is exemplified by ##STR7## and the like.

The term "loweralkyl" includes straight and branched chain hydrocarbonradicals of up to eight carbon atoms inclusive and is exemplified bysuch groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like.

The term "halogen" includes chlorine, bromine, fluorine, and iodine,preferably chlorine, bromine and fluorine.

The term "4-substituted-1-piperazinyl" refers to piperazine substitutedin the 4-position by loweralkyl or alkoxy-carbonyl blocking group whichmay subsequently be removed to give the unsubstituted piperazine.

Pharmaceutically acceptable acid addition salts are those salts formedby the pyridobenzodiazepines prepared by the process of this inventionwith any acid which is physiologically compatible in warm bloodedanimals, such salts being formed either by strong or weak acids.Representative of strong acids are hydrochloric, sulfuric and phosphoricacids. Representative of weak acids are fumaric, maleic, succinic,oxalic, cyclohexamic and the like.

The 6-aryl-11H-pyrido[2,3-b][1,4]benzodiazepines and the 5,6-dihydroderivatives thereof encompassed by Formula I have the formula: ##STR8##

The 6-aryl-11H-pyrido[3,4-b][1,4]benzodiazepines and the 5,6-dihydroderivatives thereof encompassed by Formula I have the formula: ##STR9##

The 10-aryl-5H-pyrido[4,3-b][1,4]benzodiazepines and the 10,11 dihydroderivatives thereof encompassed by Formula I have the formula: ##STR10##

The 10-aryl-5H-pyrido[3,2-b][1,4]benzodiazepines and the 10,11-dihydroderivatives thereof encompassed by Formula I have the formula: ##STR11##

In all the formulas I_(w) to I_(z), the symbols R, Ar, Z and Y have thedefinition given hereinabove under Formula I.

For the purpose of testing antidepressant activity of the presentinvention compounds, the procedure given by Englehardt, E. L., et al.,J. Med. Chem. 11(2): 325 (1968) which has been indicative in the past ofusefulness of compounds for treating human depression was used asfollows: 20 mg/kg of the compound to be tested was administered to fiveadult female mice (ICR-DUB strain) intraperitoneally 30 minutes prior tothe administration of a ptotic dose (32 mg/kg IP) of tetrabenazine (asthe methanesulfonate salt). Thirty minutes later the presence or absenceof complete eyelid closure (ptosis) was assessed in each animal. An ED₅₀(Median Effective Dose) may be established for each tested compound inblocking tetrabenazine-induced ptosis in mice following the proceduregiven by Litchfield et al., J. Pharmacol. Exp. Therap. 96: 99-113(1949).

Compounds preparable by the process of the invention or from theintermediates thereof which have antidepressant activity in theforegoing antidepressant test procedure have the Formula I_(p) ##STR12##wherein; R is selected from the group consisting of hydrogen, loweralkylor --alk¹ --N--R¹ R² ;

R¹ and R² are selected from the group consisting of hydrogen, loweralkylor R¹ and R² taken together with the adjacent nitrogen atom may form aheterocyclic residue selected from the group consisting of1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl or4-loweralkyl-1-piperazinyl;

Ar is selected from the group consisting of 2, 3 or 4-pyridinyl, 2 or3-thienyl, phenyl or phenyl substituted by 1 to 3 radicals selected fromhalo, loweralkyl, loweralkoxy, trifluoromethyl or nitro and may be thesame or different;

Alk¹ is a straight or branched hydrocarbon chain containing 1-8 carbonatoms;

Z is selected from the group consisting of hydrogen, halogen,loweralkyl, loweralkoxy, hydroxy or nitro;

Y is selected from the group consisting of hydrogen, or 1-2 radicalsselected from loweralkyl, loweralkoxy or hydroxy and may be the same ordifferent,

and the pharmaceutically acceptable acid addition salts.

The compounds of Formula I_(p) wherein R is --alk¹ --NR¹ R² and R¹ andR² are loweralkyl or hydrogen have been shown to have low incidence ofantihistaminic, anti-cholinergic and cardiotoxic side effects whentested in animals.

The preferred pyridobenzodiazepines useful in the method of treatingdepression are as follows:

Compound active ingredient (free base)

N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine.

6-(4-fluorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][(1,4]benzodiazepine-11-propanamine.

6-phenyl-1H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine.

N-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine.

6-(2-chlorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine.

6-(2-fluorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine.

The generalized schematic equation for the preparation ofpyridobenzodiazepines according to the process of the invention is givenin Chart I. ##STR13##

Compounds of Formulas I_(a), I_(b) and I_(c) are encompassed by FormulaI.

Additional procedures for converting compounds of Formulas Ia or Ibwherein Q is ##STR14## which have been separated from the reactionmixture (or which have been prepared by reacting isolated compoundswherein R³ is H with sodium hydride and reagent ##STR15## to usefulantidepressant agents (Formula VIII) are illustrated in the schematicequation of Chart II. ##STR16##

Compounds of Formula I_(e) and VI are encompassed by Formula I andFormula VIII is encompassed by I_(p).

Compounds of Formula I_(e), V and VII are novel.

Novel intermediates useful in the preparation of pyridobenzodiazepinesof Formula I have the formula: ##STR17## wherein Ar, Y and Z are thesame as defined under Formula I; X=halo (Cl, Br, F, I) and R is selectedfrom the group consisting of hydrogen, loweralkyl, --alk¹ --NR¹ R²,--alk¹ --N═CH--OC₂ H₅ or ##STR18## wherein alk¹, R¹ and R² are the sameas defined under Formula I and the acid addition salts thereof.

All positions of the pyridinyl nitrogen encompassed by Formula II areillustrated as follows: ##STR19##

Compounds of Formula II are novelly prepared according to the followinggeneralized schematic equation: ##STR20##

X=halo,

R=H or --alk¹ --Q, wherein Q=H or --NR¹ R².

Compounds of Formula II are novel.

Compounds of Formula IV are available commercially or can be readilyprepared by known methods.

Compounds of Formula III wherein R is H and corresponding to the FormulaIIIa ##STR21## are available commercially or may be prepared by knownmethods.

Novel compounds of Formula III wherein R is --alk¹ --Q and Q is H or--NR¹ R² are prepared according to the following generalized schematicequation from compounds of Formula IIIa ##STR22## wherein X is halo, Ris selected from --alk¹ NR¹ R², alk¹ --N═CH--OC₂ H₅ or ##STR23## and Ar,Z and R¹ R² are as defined under Formula I, and the acid addition saltsthereof.

It is therefore an object of the present invention to provide a novelprocess for the preparation of aryl-11H-pyrido[1,4]benzodiazepines whichare either antidepressant pharmaceutical agents or useful in thepreparation of other aryl-11H-pyrido[1,4]benzodiazepine agents whichhave antidepressant activity which utilizes a strong nucleophilic basein the condensation of (aminophenyl)arylmethanones and anamino-chloropyridine or partially condensed intermediates from thosereactants all in stirrable admixture with inert liquid carrier.

Another object is to provide novel chemical intermediates and processtherefor, such intermediates being useful in the preparation ofarylpyridobenzodiazepines, which intermediates in general terms arephenylamines linked adjacent to the amine function viaphenyl-substituted iminomethylene bridge to halopyridine and processtherefor.

Still another object is to provide certain novel(aminophenyl)arylmethanones useful as intermediates in the process ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION

The novel process of the invention for preparing compounds of Formula Iis comprised of the following four steps 1 to 4 with an optionalpreliminary step A.

Step 1, reacting a compound of the formula ##STR24## or a mixture ofcompounds of the formulas ##STR25## wherein Ar, Y and Z are as definedunder Formula I, X is halo (chlorine, bromine, fluorine or iodine), R ishydrogen or alk¹ --Q wherein alk¹ is as defined above and Q is selectedfrom hydrogen, --NR¹ R², --N═CH--OC₂ H₅, or ##STR26## and R¹ and R² areselected from loweralkyl, --C(O)O--loweralkyl or R¹ and R² takentogether with the adjacent nitrogen atom may form a heterocyclic residueselected from the group consisting of 1-piperidinyl, 1-phthalimido,1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl and4-substituted-piperazin-1-yl together with at least a stoichiometricamount of a strong non-nucleophilic alkali-metal base in stirrableadmixture with inert liquid carrier to give a compound of the formula##STR27## in stirrable admixture with inert liquid carrier, wherein Ar,Y and Z are as defined above and R³ is an alkali-metal ion selected fromsodium, potassium or lithium or --alk¹ --Q, wherein alk¹ is as definedabove and Q is the same as in the starting compound.

Step 2, optionally when desired, reacting a compound as prepared in step1 in admixture with said liquid carrier wherein R³ is an alkali-metalion with a proton source to give a compound of the formula ##STR28## inadmixture with inert liquid carrier wherein Ar, Z and Y are as definedabove.

Step 3, when desired, reacting a compound as prepared in admixture withliquid carrier in step 1 wherein R³ is an alkali-metal ion with areagent having the formula

    halo--alk.sup.1 --Q

wherein Q is selected from hydrogen, --NR¹ R², --N═CH--O--C₂ H₅, or##STR29## and R¹ and R² are selected from the group consisting ofloweralkyl, --C(O)O--loweralkyl or R¹ and R² taken together with theadjacent nitrogen atom may form a heterocyclic residue selected from thegroup consisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl,4-morpholinyl, 1-piperazinyl and 4-substituted-piperazin-1-yl, to give acompound of the formula ##STR30## in admixture with liquid carrierwherein Q has the starting value of the reagent and Ar, Y, Z and --alk¹are as defined above.

Step 4, separating a compound prepared in step 1 other than a compoundwherein R³ is an alkali-metal cation, and in steps 2 and 3 byconventional means from the carrier and the reaction mixture to give acompound of the formula ##STR31## wherein Ar, Y, Z and R are as definedabove, except R is not alkali-metal cation, and the acid addition saltsthereof.

In another novel variation of the process in a preliminary Step A,compounds of Formula II, when used in step 1, see Chart 1, are preparedas follows:

Step A, reacting a mixture of a compound of the formula ##STR32##wherein Ar, Z and R are as defined in step 1 of the formula ##STR33##wherein X is halogen and Y is as defined under Formula I, together withtitanium tetrachloride and an excess of a tertiary organic amine in aninert liquid carrier and separating the product from the reactionmixture.

Obviously, Step A also serves as a single process step for preparingcompounds of Formula II, see Chart I, which, as stated above, are novelchemical intermediates.

The following description is applicable to the foregoing process:

In step 1, suitable liquid carriers must be non-reactive with the strongnon-nucleophilic base; e.g., sodium hydride and other reactants free ofmoisture and stable enough to prevent development of alkaline metalhydroxides which lead to impurities which are difficult to remove.Carriers generally classified as strictly protic are not suitable.Suitable liquid carriers may or may not solubilize the reactants orproducts but some solubility of organic reactants and products in thecarrier is usually desirable. Examples of aprotic aromatic non-polarsolvents which are suitable as carriers are toluene, xylene and benzene.Examples of aprotic non-polar ether solvents which are suitable carriersare tetrahydrofuran, dioxane, and ethyleneglycol dimethyl ether.Examples of aprotic polar solvents which are suitable as carriers aredimethylformamide, morpholinoformamide, alkyl-2-pyrrolidinones, pyridineand dimethylsulfoxide. A preferred carrier is toluene. Use of mixturesof these carriers have been demonstrated to have advantage and suchadvantage will depend on the specific reactants or products involved,particularly when solubility is a factor. One such preferred mixtureinvolves toluene and tetrahydrofuran. Another preferred combination istoluene and dimethylformamide as in the case when the radical ##STR34##is involved. The amount of carrier may vary widely ranging from aslittle as about 5 parts per 100 parts by weight of reactants to as muchas 100 parts or more per 100 parts by weight of reactants. Generally,the minimum amount of carrier which can be used is that amount ofcarrier which will provide sufficient mobility for the reaction mixtureto become stirrable and to provide flowability to the mix. When tolueneis used, about 8-12 parts by weight of carrier to reaction mixture is apreferred range. A wide range of temperatures in step 1 may be employed,suitably about 20° C. to 150° C., about 40° C. to 120° C. beingpreferred. The more specific preferred temperature is that obtained withboiling tetrahydrofuran and refluxing toluene; i.e 65° C. to 110° C.While it is possible to conduct the reaction using a stoichiometricamount of sodium hydride, more complete reaction is obtained by using atleast one molar excess of base. Two molar equivalents of strongalkali-metal non-nucleophilic base; e.g., sodium hydride, is thereforepreferred. One preferred mode of conducting the reaction in step 1 is toslurry or dissolve the aminohalopyridine in a suitable aprotic carrier,preferably toluene, and simultaneously add a slurry of thenon-nucleophilic alkali-metal base in the same carrier and a solution ofthe aminobenzophenone in a suitable aprotic non-polar solvent,preferably tetrahydrofuran or dioxane, at a temperature such that thetetrahydrofuran boils off during the addition as the aminobenzophenoneis reacted. As indicated above, sodium, potassium or lithium hydridesare suitable strong non-nucleophilic bases which facilitate thereaction, making possible the use of the solvent carriers and arepreferred, sodium hydride being especially preferred. Among otherstrong, non-nucleophilic bases which may be used are potassium tertiarybutoxide, sodium triphenylmethane, sodium dimethylsulfoxide, andalkali-metal amides.

The following illustrates the balanced equation involved in step 1 foreach type of reactants when the strong non-nucleophilic alkali-metalbase is sodium hydride. ##STR35##

In each instance it is preferable to use an excess of sodium hydride.

In step 2, an alkali-metal salt of compounds as prepared in step 1 stillin the liquid carrier are converted to the ##STR36## compounds byreacting with any reagent capable of providing a proton source. Examplesof suitable agents are water, weak or strong acids, and water containingbuffering salts. The latter agent is preferred and the preferredbuffering salt is ammonium chloride. Blueish green color of the solutionpresent initially in this step is indicative of the sodium salt of thepyridobenzodiazepine and as the proton source is added such as aqueousammonium chloride solution, a golden yellow solid precipitates.

In step 3, the halo--alk¹ --Q reagent in a suitable organic solvent isadded to the reaction mixture containing a metal salt; i.e., R³=alkali-metal ion, and the reaction mixture is heated until reaction iscomplete. Solvents used to dissolve the reagent are generally the sameas used for the carrier in step 1, except when Q is pyranoyloxy=##STR37## halo or --N═CH--OC₂ H₅, dimethylformamide is used. Thereaction mixture is filtered to remove halo salt by-product.

In step 4, the products may be isolated, (a) by extraction, preferablyby partitioning between water and methylene chloride; (b) bychromatographic separation; (c) by conversion to acid addition salts andrecrystallizing from suitable solvent or solvent combinations; (d) bydissolving the strong acid salts such as the hydrochloride in water andextracting out impurities with a solvent such as toluene.

In preliminary step A, compounds of Formula II are substantiallyseparated from liquid carrier by conventional means such as evaporatingsolvents and partitioning between water and organic solvent, filteringto remove titanium oxide, washing, drying and evaporating the solventlayer to give the product as residue which can be used directly instep 1. The product may be further purified by chromatography orrecrystallization from organic solvents.

A preferred procedure for conducting the combination of steps 1 and 3(i.e., when step 2 is not involved) is to simultaneously add atetrahydrofuran or dioxane solution of a compound of the formula##STR38## wherein Ar, R and Z are as defined in step 1 and a slurry ofsodium hydride in toluene to a hot toluene solution of a pyridinecompound of the formula ##STR39## wherein X and Y are as defined in step1 at a rate such that the tetrahydrofuran or dioxane is distilled awayat about the same rate it is being added and thereafter adding a toluenesolution containing a reagent having the formula

    halo--alk.sup.1 --Q

wherein alk¹ and Q are as defined in step 3, except in the in theinstance where Q is ##STR40## halo or --N═CH--OC₂ H₅ in which case thesolvent for the halo--alk¹ --Q reagent preferred is dimethylformamide.

A preferred embodiment is the use in step 1 of a mixture of compounds ofsaid formulas ##STR41##

Another preferred embodiment is the use in step 1 of a mixture ofcompounds of formulas III and IV and a strong base consisting of sodiumhydride.

A further preferred embodiment is the use in step 1 of a mixture ofcompounds of formulas III and IV wherein R is H.

A still further preferred embodiment is the use in step 1 of a mixtureof compounds of formulas III and IV wherein R is H and the strong baseis sodium hydride.

Another preferred embodiment is the use in step 1 of a mixture ofcompounds of formulas III and IV consisting of 2-aminobenzophenone and3-amino-2-chloropyridine and a strong base consisting of sodium hydridein step 1 to produce the sodium salt of6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine in step 2.

As an extension of the process outlined in steps 1-4 above with orwithout optional step A, the following further optional steps (see ChartII) are novelly employed to obtain certain compounds of Formulas I andI_(p) in steps 5 to 8. As will be recognized, the generic scope ofcompounds preparable is extended to include R═OH, --alk¹ --OSO₂ --alkyl,alk¹ --OSO₂ --phenyl and one or both of R¹ and R² are H.

Step 5, reacting a novel compound obtained in step 4 of the formula##STR42## wherein Ar, Y, Z and alk¹ are as defined under Formula I witha strong concentrated acid in protic solvent, preferably ethanol, togive a novel compound of the formula ##STR43## wherein Ar, Y, Z and alk¹are as defined above.

Step 6, reacting a compound prepared in step 5 with thionyl chloride toobtain a compound of the formula ##STR44## wherein Ar, Y, Z and alk¹ areas defined above.

Step 7, reacting a compound prepared in step 5 with a reagent

    WSO.sub.2 Cl

wherein W is loweralkyl, phenyl or tolyl to give a compound of theformula ##STR45## wherein Ar, Y, Z, alk¹ and W are as defined above.

Step 8, reacting a compound prepared in steps 6 or 7 with a secondary orprimary amine of the formula

    HNR.sup.1 R.sup.2

wherein R¹ and R² are selected from hydrogen, loweralkyl, and --NR¹ R²may be a heterocyclic radical as defined under Formula I, to give acompound of the formula ##STR46## wherein Ar, Y, Z, alk¹ and R¹, R² and--NR¹ R² are as defined above.

Primary amines may be prepared by reacting compounds wherein --NR¹ R² isphthalimido with hydrazine hydrate and acid ##STR47##

Compounds prepared by the process wherein Q is --NHC(O)O-loweralkyl maybe reacted with lithium aluminum hydride to prepare secondary amines ofthe formula ##STR48##

Compounds wherein Q is --N═CH--OC₂ H₅ may also be reacted with sodiumborohydride to prepare secondary amines.

The following preparations 1 and 2 illustrate the method for preparingaryl-(2-amino-substituted-phenyl)methanone of Formula III wherein R isother than hydrogen (see Chart II) and are not to be construed as beinglimiting in nature.

Preparation 1 [2-[[3-(Dimethylamino)propyl]amino]phenyl]phenylmethanonemonohydrochloride

To a mixture of 78.8 g (0.4 mole) of 2-aminobenzophenone, 160 g (4.0mole) of crushed sodium hydroxide and 8 g of tetra-n-butyl ammoniumbromide was added a dry solution of 145.8 g (1.2 mole) of3-dimethylaminpropyl chloride in 700 ml of tetrahydrofuran. The mixturewas stirred mechanically and was maintained at reflux overnight. Thetetrahydrofuran solution was decanted and concentrated. The concentratewas dissolved in toluene. The solid from which the tetrahydrofuran wasdecanted was dissolved in water and extracted with the toluene solution.The resulting toluene layer was separated and washed twice with waterand then extracted three times with portions of 20% acetic acid totaling600 ml. The combined acetic acid solution was washed once with tolueneand then made basic with 50% sodium hydroxide in the presence oftoluene. The aqueous layer was separated and extracted once withtoluene. The toluene layers were combined and washed with water, driedover sodium sulfate and evaporated to give 112.8 g (100%) of nearly purefree base of the title compound. A 20 g sample was dissolved in 75 ml ofisopropyl alcohol to which was added 0.076 mole of hydrogen chloridedissolved in about 35 ml isopropyl alcohol. Additional isopropyl alcoholand isopropyl ether (about 1:1 ratio) were added to make a total volumeof about 200 ml. The mixture was stirred overnight. The yellow solid wascollected by filtration, washed once with 1:1 isopropylalcohol/isopropyl ether and twice with isopropyl ether. Weight ofproduct obtained from the 20 g sample was 16.4 g, m.p. 182°-183° C.

Analysis:

Calculated for C₁₈ H₂₃ N₂ OCl: C,67.81; H, 7.27; N,8.79

Found: C,67.68; H,7.29; N,8.70

Preparation 2

Following the procedure of Preparation 1 but substituting the followingfor 3-dimethylaminopropyl chloride,

3-(1-pyrrolidinyl)propylamine,

3-(1-piperidinyl)propylamine, and

3-(4-morpholinyl)propylamine,

there are obtained:

[2-[[3-(1-pyrrolidinyl)propyl]amino]phenyl]phenylmethanone,

[2-[[3-(1-piperidinyl)propyl]amino]phenyl]phenylmethanone, and

[2-[[3-(4-morpholinyl)propyl]amino]phenyl]phenylmethanone.

The following examples are provided merely by way of illustration andare not to be construed as being limiting in nature.

EXAMPLE 1 N-[(2-Aminophenyl)phenylmethylene]-2-chloro-3-pyridinamine

To a stirred suspension of 3.94 g (0.02 mole) of 2-aminobenzophenone and2.58 g (0.02 mole) of 3-amino-2-chloropyridine in 20 ml of toluene and6.2 ml (0.048 mole) of triethylamine under a nitrogen blanket in an icebath was added a solution of 2.28 g (0.012 mole) of titaniumtetrachloride in 10 ml of toluene over a 5 min period. After theaddition was complete, the ice bath was removed. The mixture became darkred in color and solid material was in evidence. About 15 ml of toluenewas added followed by 15 ml of methylene chloride. After 1 hr totaltime, TLC showed starting material and product were present. After 3 hrtotal time, additional titanium chloride, 1.52 g (0.08 mole), in 4.15 ml(0.032 mole) of triethylamine and methylene chloride was added to thereaction mixture which was then stirred overnight. The mixture wasevaporated. The residue was partitioned between water and methylenechloride. Solid precipitate was removed by filtration. The aqueous layerwas separated and extracted again with methylene chloride. The methylenechloride layers were combined and back washed with sodium chloridesolution, dried over sodium sulfate and evaporated to give 6.2 g oforange oil. The chemical ionization mass spectrometer gave product peakat m/e 308 and starting materials peaks at m/e 198 and m/e 129. NMRanalysis as follows indicated the product was composed of about 75% ofthe title compound. The ¹ HNMR spectrum of the crude subject product wasobtained in CDCl₂ containing 1% tetramethylsilane (TMS). The chemicalshifts, multiplicities and assignments are given below. ##STR49##

    ______________________________________                                        Chemical Shifts                                                               (multiplicities)                                                              at ppm             Assignments                                                ______________________________________                                        7.50     (multiplet)   Ha in Compound A                                       7.35     (multiplet)   Hb in Compound B                                       7.30-5.95                                                                              (multiplet)   signals from other                                                            protons attached to                                                           carbons on Compounds                                                          A, B and C                                             5.40 4.83                                                                              (broad singlet) (singlet)                                            ______________________________________                                         Ratio of the integrations at 7.50 ppm to that at 7.35 ppm is roughly 3:1,     thus the product is about 75% A.

EXAMPLE 2 N-[(2-Aminophenyl)phenylmethylene]-2-chloro-3-pyridinamine

To a stirred suspension of 7.88 g (0.04 mole) of 2-aminobenzophenone and5.14 g (0.04 mole) of 3-amino-2-chloropyridine in 100 ml of methylenechloride and 27.2 ml (0.2 mole) of triethylamine under nitrogen blanketwas added a solution of 5.28 ml of titanium tetrachloride in 20 ml ofmethylene chloride dropwise over a 10 min period. The reaction mixturewas stirred at room temperature for 22 hr. Water was added slowly to thereaction mixture until a thick suspension was formed. The suspension waspoured into 150 ml of water and the resulting mixture was stirred for 15min. The mixture was filtered to remove titanium dioxide. The filtercake was rinsed with methylene chloride. The organic layer of thefiltrate was separated. The aqueous layer was extracted once withmethylene chloride. The methylene chloride layers were combined, washedwith dilute sodium bicarbonate solution, dried and evaporated to give12.6 g of brown syrup. NMR analysis as follows indicated the product wascomposed mainly of title compound with about 15%3-amino-2-chloropyridine starting material contaminant. The ¹ HNMRspectrum of the crude subject product was obtained in CDCl₃ containing1% tetramethylsilane (TMS). The chemical shifts, multiplicities andassignments are given below. ##STR50##

    ______________________________________                                        Chemical Shifts                                                               (multiplicities)                                                              at ppm            Assignments                                                 ______________________________________                                        7.70     (multiplet)  Ha in Compound A                                        7.55     (multiplet)  Hb in Compound B                                        5.55     (broad singlet)                                                      5.00     (singlet)                                                                                   ##STR51##                                              7.40-610 (multiplet)  signals from remainder                                                        of protons on Compounds                                                       A, B and C.                                             ______________________________________                                    

Ratio of the integrations at 7.70 ppm to that at 7.55 ppm is roughly 13to 2; thus the product is about 85% A.

EXAMPLE 3

Following the procedure of Example 2 but substituting the following for3-amino-2-chloropyridine,

4-amino-3-chloropyridine,

3-amino-4-chloropyridine, and

2-amino-5-chloropyridine

there are obtained:

(a) N-[(2-aminophenyl)phenylmethylene]-3-chloro-4-pyridineamine,

(b) N-[(2-aminophenyl)phenylmethylene]-4-chloro-3-pyridinamine, and

(c) N-[(2-aminophenyl)phenylmethylene]-3-chloro-2-pyridinamine.

EXAMPLE 4

Following the procedure of Example 2 but substituting the following for2-aminobenzophenone,

2-amino-4-chlorobenzophenone,

2-amino-4-methylbenzophenone,

2-amino-4-methoxybenzophenone,

2-amino-4-hydroxybenzophenone,

2-amino-4-nitrobenzophenone,

2-amino-5-chlorobenzophenone,

2-amino-4'-chlorobenzophenone, and

2-amino-4'-methylbenzophenone,

there are obtained:

(a) N-[(2-amino-4-chlorophenyl)phenylmethylene]-2-chloro-3-pyridinamine,

(b)N-[(2-amino-4-methylphenyl)phenylmethylene]-2-chloro-3-pyridineamine,

(c)N-[(2-amino-4-methoxyphenyl)phenylmethylene]-2-chloro-3-pyridinamine,

(d)N-[(2-amino-4-hydroxyphenyl)phenylmethylene]-2-chloro-3-pyridinamine,

(e) N-[(2-amino-4-nitrophenyl)phenylmethylene]-2-chloro-3-pyridinamine,

(f) N-[(2-amino-5-chlorophenyl)phenylmethylene]-2-chloro-pyridinamine,

(g) N-[(2-aminophenyl)-4-chlorophenylmethylene]-2-chloro-3-pyridinamine,and

(h) N-[(2-aminophenyl)-4-methylphenylmethylene]-2-chloro-3-pyridinamine.

EXAMPLE 5N'-[2-[(2-Chloro-3-pyridinylimino)phenylmethyl]phenyl]-N,N-dimethyl-1,3-propanediamine

To a mixture of 2.82 g (0.01 mole) of[2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone and 1.29 g(0.01 mole) of 3-amino-2-chloropyridine, 6.2 ml (0.048 mole) oftriethylamine and 20 ml of methylene chloride stirred in an ice bathunder nitrogen atmosphere was added 2.28 g (0.012 mole) of titaniumtetrachloride in 10 ml of methylene chloride during a 5 minute period.The mixture was then stirred at room temperature for 2 days during whichtime mass spec-CI showed little change in relative intensity of M.W. 129(starting pyridine) and M.W. 393 (title product). Water was added to thereaction mixture and stirring was continued for 1.5 hr. The mixture wasfiltered to remove solid and the filter cake was rinsed with methylenechloride. Saturated sodium chloride solution was added to facilitateseparation of layers. The methylene chloride layer was washed once withmore sodium chloride solution. The aqueous layer having a pH of about 6was basified to about pH 8-9 with potassium carbonate and then extractedtwice with methylene chloride. The latter methylene chloride layers werewashed with sodium chloride solution. All the methylene chlorideextracts were combined, dried and evaporated to give 4.8 g of semi-solidproduct. TLC of the product showed it contained evey little starting3-amino-2-chloropyridine. Mass Spec. analysis showed the presence ofcompounds with molecular weight corresponding to title product (393),3-amino-2-chloropyridine (129) and triethylamine (102) but no[2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone. ¹ HNMRspectrum in CDCl₃ containing 1% TMS indicated the product was mostlytitle compound and some triethylamine. No 3-amino-2-chloropyridine wasseen. The chemical shifts, multiplicities and assignments are givenbelow. ##STR52##

    ______________________________________                                        Chemical Shifts                                                               (multiplicities)                                                              at ppm            Assignments                                                 ______________________________________                                        9.85-9.40 (multiplet) N --H on A as well as                                                         (Et).sub.3 N.sup.+.H                                    7.85      (multiplet) Ha                                                      7.50-6.23 (multiplet) protons attached to                                                           aromatic rings                                          5.25      (singlet)                                                           2.25      (singlet)                                                                                  ##STR53##                                              3.70-1.70 (multiplet) signals from alkylene                                                         groups (--CH.sub.2 --) on                                                     compound  --A as well as                                                      triethylamine                                           1.35      (triplet)   methyl group signals                                                          on triethylamine                                        ______________________________________                                    

EXAMPLE 6N'-[2-[(2-Chloro-3-pyridinylimino)phenylmethyl]phenyl]-N,N-dimethyl-1,3-propanediamine

To a mixture of 6.37 g (0.02 mole) of[2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone and 2.57 g(0.02 mole) of 3-amino-2-chloropyridine, 16.8 ml (0.12 mole) oftriethylamine in 80 ml of methylene chloride stirred in an ice bathunder nitrogen atmosphere was added dropwise 2.64 ml (0.024 mole) oftitanium tetrachloride in 20 ml of methylene chloride over a 10 minperiod. The mixture was allowed to cool to room temperature withcontinued agitation. The following day chemical ionization massspectrometry showed that the reaction had essentially gone to completionwith no starting methanone compound present. TLC showed little of thestarting pyridine was present. The mixture was stirred over the weekend.Water was added to the reaction mixture and stirring was continued for1.5 hr. The mixture was filtered to remove solid and filter cake wasrinsed with methylene chloride. Saturated sodium bicarbonate solutionwas added to facilitate separation of layers. The methylene chloridelayer was washed once with more bicarbonate solution. The aqueous layerwas washed with methylene chloride and all the methylene chlorideextracts were combined, dried and evaporated to give 7.35 g (93.5%) ofbrown oil. The chemical ionization mass spectrometer gave a signalcorresponding to a molecular weight of the title compound at m/e 393.5and showed a trace of compound at m/e 282 (starting methanone free base)and some compound at m/e 102 (triethylamine) and some compound at m/e129.5 (starting amino-chloropyridine). The ¹ HNMR spectrum of thesubject product was obtained in CDCl₃ containing 1% tetramethylsilane(TMS) and is consistent with the proposed structure and with methylenechloride as minor impurity. No signal from starting materials weredetected. The chemical shifts, multiplicities and assignments are givenbelow. ##STR54##

    ______________________________________                                        Chemical Shifts                                                               (multiplicities)                                                              at ppm               Assignments                                              ______________________________________                                        9.55       (broad singlet)                                                                             Hb                                                   7.85       (multiplet)   Ha                                                   7.50 to 6.25                                                                             (multiplet)   Haromatic                                            5.20       (singlet)                                                          3.50 to 3.15                                                                             (quartet)     e -                                                  2.15       (singlet)     f .sub.-                                             2.55 to 1.70                                                                             (multiplet)                                                                                  ##STR55##                                           ______________________________________                                    

EXAMPLE 76-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-pyranoyloxypropyl

To a solution of 10.82 g (0.04 mole) of6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine in 60 ml ofdimethylformamide was added 3.2 g (0.08 mole) of sodium hydride as 60%suspension in mineral oil followed by 13.2 ml (0.08 mole) of1-chloro-3-pyranoyloxypropane. Progress of the reaction was followed viaTLC and an additional 0.7 g of 60% sodium hydride was added. After thereaction had stirred for about 3 days, a trace of startingpyridobenzodiazepine remained. The reaction mixture was treated withaqueous ammonium chloride and extracted three times with toluene. Thetoluene layer was back-washed with water, dried, treated with activatedcharcoal and filtered. The filtrate was evaporated to give 22.8 g ofblack oil. The oil was passed through a short column of 45 g silica gel,eluting first with toluene and then toluene-ethyl acetate. Fraction Awas concentrated to give 16.3 g of a mixture consisting of 85% titleproduct and 15% 1-chloro-3-pyranoyloxy propane+mineral oil+toluene.Fraction B was concentrated to give 2.4 g residue. Mass spectra ofFraction A showed the following:

m/e 179 which is starting 1-chloro-3-pyranoyloxy propane used in excess,

m/e 330 which is a fragment from the product, and

m/e 414 which is the title product.

The ¹ HNMR spectrum of the subject crude product was obtained and isconsistent with the proposed structure and with toluene and1-chloro-3-pyranoyloxypropane. The chemical shifts, multiplicities andassignments are given below. ##STR56##

    ______________________________________                                        Chemical Shifts                                                               (multiplicities)                                                              at ppm              Assignments                                               ______________________________________                                        8.15      (multiplet)   Ha                                                    7.95-6.90 (multiplet)   remainder of aromatic                                                         protons                                               4.58      (broad singlet)                                                                             Hb                                                    4.48      (broad singlet)                                                                             Hc                                                    4.25      (multiplet)   d protons                                             2.35      (singlet)     e protons                                             2.25-1.15 (multiplet)   f protons                                             ______________________________________                                    

EXAMPLE 8 6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-hydroxypropyl

A mixture of 3.6 g (0.0088 mole) of6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-pyranoyloxypropyl, 3.6ml of 37% aqueous hydrochloric acid and 15 ml of 190 proof ethanol wasstirred overnight. Sodium hydroxide pellets, 1.7 g, was added and themixture stirred until the pellets had disintegrated. The solvent wasevaporated and the residue was partitioned between methylene chlorideand water. The aqueous layer was extracted once more with methylenechloride. The combined methylene chloride layers were washed with water,dried and evaporated to give 2.93 g of brown oil which crystallized. Thecrystals were separated by filtration and washed with isopropylether-petroleum ether. On drying, the yellow crystals weighed 1.91 g,m.p. 131°-134° C. Mass spectra of the product showed the following:

m/e 103 which is isopropyl ether which was used as crystallizationsolvent,

m/e 414 which is starting material, trace amount, and

m/e 330 which is title product.

The ¹ H NMR spectrum of the subject crystalline product was obtained andis consistent with the proposed structure ##STR57## The chemical shifts,multiplicities and assignments are given below.

    ______________________________________                                        Chemical Shifts                                                               (multiplicities)                                                              at ppm                Assignments                                             ______________________________________                                        8.20-6.80                                                                              (multiplet)      all aromatic protons                                4.45-3.50                                                                              (multiplet)      a protons                                           3.65     (where triplet centered)                                                                       b protons                                           2.65     (singlet)        d protons                                           2.15-1.65                                                                              (multiplet)      c protons                                           1.10     (doublet)        e protons                                           ______________________________________                                    

EXAMPLE 9N'-[2-Chloro-6-[(3-chloro-4-pyridinylimino)phenylmethyl]phenyl]-N,N-dimethyl-1,3-propanediamine

Following the procedure of Example 6 and substituting[2-[[3-(dimethylamino)propyl]amino]-6-chlorophenyl]phenylmethanone, thetitle compound is prepared.

EXAMPLE 10 6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine Sodium Salt(Crude Mixture)

To a solution of 516 g (4 mole) of 3-amino-2-chloropyridine in 3.8liters of toluene were added simultaneously in batches a solution of 830g (4.2 mole) of 2-aminobenzophenone in 2.2 liters of pyridine and aslurry of 290 g (12 mole) (as 60% in mineral oil) of sodium hydrideslurried in 500 ml of toluene over a 2 hr period at reflux. Refluxcontinued for 3 hr additional. Evolution of hydrogen was vigorous. Afterstirring overnight at ambient temperature, the mixture was heated toremove a volume of distillate of 3.8 liters which NMR indicated to be65% toluene and 35% pyridine.

EXAMPLE 11 6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine

To the residual mixture in Example 10 was added cautiously a solution of440 g (8 mole) of ammonium chloride in 700 ml of water (much foaming).The mixture was heated to remove 1.5 liters of distillate comprised ofwater, pyridine and toluene. To the residual solution was added 500 mlof toluene and the mixture heated a second time to remove 900 ml ofdistillate. To the residual solution 500 ml more toluene was added andthe mixture was again heated to remove 500 ml of distillate. The orangeresidual slurry was diluted with 7.2 liters of tetrahydrofuran. Themixture was filtered. The cake was washed by slurrying in 3 liters ofhot tetrahydrofuran and the slurry filtered. The filtrates were combinedand passed through a silica gel column. The eluent was concentrated andthe residue slurried in isopropyl ether-toluene [3:1]. Brown-orangesolid was collected by filtration. The filtrate was concentrated andazeotroped with toluene to remove pyridine The residual solution wasdiluted with isopropyl ether-toluene [1:1] and the solution wasrefrigerated to obtain yellow crystals. The combined yield of the titlecompound was 813 g (75%) based on starting materials in Example 10. TLCanalysis of the product gave a good comparative result with known titleproduct.

EXAMPLE 12N,N-Dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamineFumarate [1:1]

A mixture of 920 g (3.4 mole) of6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine prepared in Example 11(and another small run) in 2 liters of toluene and 1.5 liter oftetrahydrofuran and 84 g (3.5 mole) of sodium hydride (as 60% in mineraloil) was heated at reflux with vigorous evolution of hydrogen. Themixture became black-green in color. To the mixture was added a solutionof 7.6 mole of 3-dimethylaminopropyl chloride in 2 liters of toluene andthe reaction mixture was heated at reflux for 5 hr and then cooledovernight. The black-yellow mixture was filtered with difficulty mainlyto remove sodium chloride. The filtrate was concentrated to remove allbut about 1.5-2 liters of toluene. The residual toluene concentrate wasdiluted with 2 liters of methylene chloride and the solution washed withwater. The washed solution was concentrated on a rotary evaporator at80° C. bath temperature. The remaining black syrup weighed 1400 g. Thesyrup was poured slowly into a hot solution of 394 g (3.4 mole) offumaric acid in 4 liters of isopropyl alcohol. The solution was treatedwith activated charcoal and filtered. The filtrate was seeded andrefrigerated overnight. The yellow precipitate was collected byfiltration and washed with a small amount of isopropyl ether and driedto give 1491 g (93%) of the fumarate salt. The salt was dissolved in17.2 liters of isopropyl alcohol and the solution was treated with 75 gof charcoal heated at reflux for 15 min and filtered through a columncontaining 100 g of Celite which had been wetted with 200 ml ofisopropyl alcohol. The filtrate was then stirred for 20 hr. Theprecipitate was collected by filtration, washing the filter cake withcold isopropyl alcohol followed by 3 liters of isopropyl ether and driedto give 1255 g (85%) of crystalline product. The crystals weretriturated with 1 liter of isopropyl ether-methylene chloride (3:1 byvol.) and the mixture subjected to filtration. The cake was vacuum driedat 60° C. overnight under high vacuum, m.p. 174°-175° C., uncorrected.

Analysis:

Calculated for C₂₇ H₂₈ N₄ O₄ : C,68.63; H,5.97; N,11.86

Found: C,68.48; H,6.00; N,11.80

EXAMPLE 13N,N-Dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanemineFumarate [1:1] Preparation of Crude Free Base of Title Compound

To a solution of 780 g (6 mole) of 3-amino-2-chloropyridine in 2 litersof toluene at reflux was added simultaneously a solution of 1,320 g (6.6mole) of 2-aminobenzophenone in 3 liters of tetrahydrofuran and a slurryof 444.0 g (18.5 mole) of sodium hydride in 1.2 liters of toluene over a3 hr period. (During the addition at reflux, the tetrahydrofurandistilled out at about the same rate it was being added). To thereaction mixture was added 12 moles of 3-dimethylaminopropyl chloride in3.5 liters of toluene. The mixture was heated at reflux for 5 hr thenwas allowed to cool, standing overnight at ambient temperature. TLCindicated some 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine waspresent; therefore, 12 g more sodium hydride was added and the mixturewas heated at reflux to complete the reaction. The mixture was allowedto cool somewhat and 2 liters of saturated ammonium chloride and 3liters of water were added. The aqueous layer was discarded and thetoluene layer was washed four times with 2 liters of water each time.The toluene layer was concentrated on a rotary evaporator and finallysubjected to high vacuum distillation to remove unreacted3-dimethylaminopropyl chloride. Yield of crude syrup containingprimarily the free base of the title compound was 2,680 g.

Conversion to Fumarate Salt and Purification Thereof

The crude syrup was mixed with 6 moles of fumaric acid in 10 liters ofisopropyl alcohol. The precipitate was collected and washed with 3liters of isopropyl alcohol and recrystallized twice to give 2,200 g ofyellow crystals. A sample triturated with a mixture of hot isopropylether-methylene chloride [3:1 by volume] gave the following analysis:

Analysis:

Calculated for C₂₇ H₂₈ N₄ O₄ : C,68.63; H,5.97; N,11.86

Found C,68.23; H,5.99; N,11.87

EXAMPLE 14N,N-Dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamineFumarate [1:1] Preparation of Crude Free Base of Title Compound

To a solution of 129 g (1 mole) of 3-amino-2-chloropyridine in 350 ml oftoluene at reflux was added simultaneously a solution of 217 g (1.1mole) of 2-aminobenzophenone in 500 ml of tetrahydrofuran and a slurryof 74.5 g (3.1 mole) of sodium hydride in 250 ml of toluene over a 1.5hr period. (During the addition at reflux the tetrahydrofuran distilledout at about the same rate it was being added). To the reaction mixturewas added 2 moles of 3-dimethylaminopropyl chloride in 600 ml oftoluene. The mixture was heated at reflux for 5 hr.

To the black slurry comprised of free base of the title compound andsome unreacted sodium hydride and 3-dimethylaminopropyl chloride intoluene (shown by TLC to be free of any6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine) was added 1 mole ofammonium chloride in 800 ml of water. The organic layer was separatedand washed with four 500 ml portions of water. The organic layer wasconcentrated on a rotoevaporator to remove solvent and under high vacuumto remove unreacted 3-dimethylaminopropyl chloride. Yield of darkbrown-yellow syrup comprised principally of free base of the titlecompound was 433 g.

Conversion to Fumarate Salt

The syrup was dissolved in 800 ml of isopropyl alcohol and to thesolution was added 1 mole of fumaric acid in 1.5 liters of isopropylalcohol. The salt crystallized by seeding and separated by filtration.

EXAMPLE 15 6-(2-Thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

Following the procedures of Examples 10 and 11 but substituting2-aminophenyl-(2-thienyl)methanone in Example 10 for2-aminobenzophenone, the title compound is obtained.

EXAMPLE 16 6-(3-Thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

Following the procedures of Examples 10 and 11 but substituting2-aminophenyl-(3-thienyl)methanone in Example 10 for2-aminobenzophenone, the title compound is obtained.

EXAMPLE 17 6-(2-Pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

Following the procedures of Examples 10 and 11 but substituting2-aminophenyl-(2-pyridinyl)methanone for 2-aminobenzophenone in Example10, the title compound is obtained.

EXAMPLE 18 6-(3-Pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

Following the procedures of Examples 10 and 11 but substituting2-aminophenyl-(3-pyridinyl)methanone for 2-aminobenzophenone in Example10, the title compound is obtained.

EXAMPLE 19 6-(4-Pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

Following the procedures of Examples 10 and 11 but substituting2-aminophenyl-(-pyridinyl)methanone for 2-aminobenzophenone in Example10, the title compound is obtained.

EXAMPLE 20

Following the procedure of Example 12 but substituting the following for6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine:

6-(2-thienyl)-1H-pyrido[2,3-b][1,4]benzodiazepine,

6-(3-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

6-(2-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

6-(3-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

and, 6-(4-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

there are obtained:

(a)N,N-dimethyl-6-(2-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate,

(b)N,N-dimethyl-6-(3-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate,

(c)N,N-dimethyl-6-(2-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate,

(d)N,N-dimethyl-6-(3-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate, and

(e)N,N-dimethyl-6-(4-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate.

EXAMPLE 21

Following the procedure of Example 5 but substituting the following for[2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone:

[2-[[3-(1-pyrrolidinyl)propyl]amino]phenyl]phenylmethanone,

[2-[[3-(1-piperidinyl)propyl]amino]phenyl]phenylmethanone, and

[2-[[3-(4-morpholinyl)propyl]amino]phenyl]phenylmethanone,

there are obtained:

N-[2-[(2-chloro-3-pyridinylimino)-3-(1-pyrrolidinyl)propanamine,

N-[2-[(2-chloro-3-pyridinylimino)-3-(1-piperidinyl)propanamine, and

N-[2-[(2-chloro-3-pyridinylamino]-3-(4-morpholinyl)propanamine,

EXAMPLE 22N,N-Dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamineFumarate [1:1]

To a solution of 2.5 g (0.00637 mole) ofN'-[2-[(2-chloro-3-pyridinylimino)phenylmethyl]phenyl]-N,N-dimethyl-1,3-propanediamineobtained in Example 5 in 20 ml of toluene (solution was dried byazeotroping using a Dean Stark trap and cooled) was added 0.62 g (0.0128mole) of sodium hydride as 50% mineral oil suspension added to a smallamount of toluene. The mixture was heated at reflux for 3 hr. Water wasadded cautiously. The toluene layer was washed twice with water andextracted twice with 1N aqueous hydrochloric acid solution. The aqueousacidic layer was washed with toluene. The aqueous layer was thenbasified with 50% sodium hydroxide solution in the presence of toluene.The aqueous layer was extracted twice with toluene. The toluene layerswere combined, charcoaled, filtered and evaporated to give 2.03 g ofbrown oil, the free base of the title compound (89.5% yield). The oilwas dissolved in isopropyl alcohol and 0.7 g fumaric acid was added withwarming. The solution was seeded with known title compound and allowedto stand about 15 hr at room temperature. Isopropyl ether was added withstirring for 15 min. The solid was collected by filtration and washedonce with isopropyl alcohol-isopropyl ether mix and once with isopropylether. On air drying, 2.4 g (80%), m.p. 168°-170° C. was obtained. Themelting point, NMR analysis and Mass Spec. analysis were comparable toknown title compound.

EXAMPLE 23

Following the procedure of Example 22 but substituting the following forN'-[2-[(2-chloro-3-pyridinylimino)phenylmethyl]phenyl]-N,N-dimethyl-1,3-propanamine:

N-[2-[(2-chloro-3-pyridinylimino)-3-(1-pyrrolidinyl)propanamine,

N-[2-[(2-chloro-3-pyridinylimino)-3-(1-piperidinyl)propanamine, and

N-[2-[(2-chloro-3-pyridinylimino)-3-(4-morpholinyl)propanamine,

there are obtained:

6-phenyl-11-[3-(1-pyrrolidinyl)propyl]-11H-pyrido[2,3-b][1,4]benzodiazepinefumarate,

6-phenyl-11-[3-(1-piperidinyl)propyl]-11H-pyrido[2,3-b][1,4]benzodiazepinefumarate, and

6-phenyl-11-[3-(4-morpholinyl)propyl]-11H-pyrido[2,3-b][1,4]benzodiazepinefumarate, using ethanol-ethyl acetate recrystallizing solvent in thelatter.

What is claimed is:
 1. A process for the preparation of apyridobenzodiazepine compound having the formula: ##STR58## wherein; Ris selected from the group consisting of alkali-metal cation (M⁺),hydrogen, --alk¹ --Q wherein Q is selected from hydrogen, halo, --NR¹R², --N═CH--OC₂ H₅ or ##STR59## R¹ and R² are selected from the groupconsisting of loweralkyl, --C(O)--O--loweralkyl or R¹ and R² takentogether with the adjacent nitrogen atom may form a heterocyclic residueselected from the group consisting of 1-piperidinyl, 1-phthalimido,1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl and4-substituted-piperazin-1-yl;Ar is selected from the group consisting of2, 3 and 4-pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted by 1to 3 adicals selected from halo, loweralkyl, loweralkoxy,trifluoromethyl or nitro and may be the same or different; alk¹ is astraight or branched hydrocarbon chain containing 1-8 carbon atoms; Z isselected from the group consisting of hydrogen, halogen, loweralkyl,loweralkoxy, hydroxy or nitro; Y is selected from the group consistingof hydrogen or 1-2 radicals selected from loweralkyl, loweralkoxy orhydroxy and may be the same or different, and the acid addition saltsthereof except when R=M⁺, which comprises the steps of: Step 1, reactinga compound of the formula ##STR60## or a mixture of compounds of theformulas ##STR61## wherein Ar, Y and Z are as defined above and X isselected from chlorine, bromine, fluorine or iodine; R is hydrogen oralk¹ --Q wherein alk¹ is as defined above and Q is hydrogen, --NR¹ R²,--N═CH--OC₂ H₅ or ##STR62## and R¹ and R² are selected from loweralkyl,--C(O)O--loweralkyl, or R¹ and R² taken together with the adjacentnitrogen atom may form a heterocyclic residue selected from the groupconsisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl,4-morpholinyl, 1-piperazinyl and 4-substituted-piperazin-1-yl, with atleast a stoichiometric amount of a strong non-nucleophilic alkali-metalbase in stirrable admixture with inert liquid carrier to give a compoundof the formula ##STR63## in said carrier, wherein Ar, Y and Z are asdefined above, and R³ is an alkali-metal ion consisting of sodium,potassium or lithium, or --alk¹ --Q wherein alk¹ is as defined above andQ is the same as in the starting compound; Step 2, reacting a compoundas prepared in said carrier in step 1 wherein R³ is an alkali-metal ionwith a proton source to give a compound of the formula: ##STR64## insaid carrier, wherein Ar, Z and Y are as defined above. Step 3, reactinga compound as prepared in said carrier in step 1 wherein R³ is analkali-metal ion with a reagent having the formula:

    halo--alk.sup.1 --Q

wherein Q is selected from hydrogen, --NR¹ R², --N═CH--O--C₂ H₅ or##STR65## and R¹ and R² are as selected from the group consisting ofloweralkyl, --C(O)--O--loweralkyl or R¹ and R² taken together with theadjacent nitrogen atom may form a heterocyclic residue selected from thegroup consisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl,4-morpholinyl, 1-piperazinyl and 4-substituted-piperazin-1-yl, to give acompound of the formula: ##STR66## in said carrier, wherein Q has thestarting value of said reagent and Ar, Y, Z and alk¹ are as definedabove; Step 4, separating a compound prepared in step 1, other than acompound wherein R³ is an alkali-metal cation or a compound prepared insteps 2 or 3 by conventional means from said carrier and the reactionmixture to give a compound of the formula: ##STR67## wherein Ar, Y, Zand R are as defined above, except R is not alkali-metal ion, and theacid addition salts thereof.
 2. The process of claim 1 wherein in step1, compounds of said formulas ##STR68## are reacted with said strongbase.
 3. The process of claim 1 wherein in step 1, compounds of saidformulas ##STR69## are reacted with said strong base consisting ofsodium hydride.
 4. The process of claim 1 wherein in step 1 a mixture ofcompounds of said formulas ##STR70## wherein R is H are reacted withsaid strong base.
 5. The process of claim 1 wherein in step 1 a mixtureof compounds of said formulas ##STR71## wherein R is H are reacted withstrong base consisting of sodium hydride.
 6. The process of claim 1wherein in step 1 a mixture of compounds of said formulas ##STR72##consisting of 2-aminobenzophenone, and3-amino-2-chloropyridine arereacted with sodium hydride to give in step 1 the sodium salt of6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine.
 7. The process of claim 1wherein in step 1 a mixture of compounds of said formulas ##STR73##consisting of [2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone,and3-amino-2-chloropyridine are reacted with sodium hydride in step 1 togiveN,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine.8. The process of claim 1 wherein in step 1, a compound of said formula##STR74## is reacted with said strong base.
 9. The process of claim 1wherein in step 1, a compound of said formula ##STR75## is reacted withsaid strong base consisting of sodium hydride.
 10. The process of claim1 wherein in step 1, a compound of said formula ##STR76## consisting ofN-[(2-aminophenyl)phenylmethylene]-2-chloro-3-pyridinamine is reactedwith said strong base.
 11. The process of claim 1 wherein atetrahydrofuran solution of a compound of said formula ##STR77## and aslurry of sodium hydride in toluene are added simultaneously to aboiling toluene solution of pyridine compound of said formula ##STR78##at a rate such that tetrahydrofuran or dioxane is distilled off at aboutthe same rate it is being added and thereafter adding a toluene solutioncontaining a reagent having said formula

    halo--alk.sup.1 --Q

to give a compound having said formula ##STR79##
 12. The process ofclaim 1 wherein in a preliminary step A, a compound of said formula##STR80## in said liquid carrier is prepared by reacting a mixture of acompound of said formula ##STR81## and a compound of said formula##STR82## together with titanium tetrachloride and an excess of atertiary organic amine in an inert liquid carrier and substantiallyseparating the product from the reaction mixture by conventional meansand using the product in said step
 1. 13. A process for the preparationof a pyridobenzodiazepine compound having the formula: ##STR83##wherein; R is selected from the group consisting of an alkali-metalcation, hydrogen, --alk¹ --Q wherein Q is selected from hydrogen, halo,--NR¹ R², --N═CH--OC₂ H₅, ##STR84## hydroxy or --OSO₂ W wherein W isloweralkyl, phenyl or tolyl; R¹ and R² are selected from the groupconsisting of hydrogen, loweralkyl, --C(O)--O--loweralkyl or R¹ and R²taken together with the adjacent nitrogen atom may form a heterocyclicresidue selected from the group consisting of 1-piperidinyl,1-phthalimido, 1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl and4-substituted-piperazin-1-yl;Ar is selected from the group consisting of2, 3 and 4-pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted by 1to 3 radicals selected from halo, loweralkyl, loweralkoxy,trifluoromethyl or nitro and may be the same or different; alk¹ is astraight or branched hydrocarbon chain containing 1-8 carbon atoms; Z isselected from the group consisting of hydrogen, halogen, loweralkyl,loweralkoxy, hydroxy or nitro; Y is selected from the group consistingof hydrogen or 1-2 radicals selected from loweralkyl, loweralkoxy orhydroxy and may be the same or different, comprising the steps of StepA, reacting a mixture of a compound of the formula ##STR85## wherein Ar,Z and R are as defined above in this claim, except R is neveralkali-metal ion and Q is never halo, hydroxy or --OSO₂ W, and R¹ and R²are not hydrogen, and a compound of the formula ##STR86## wherein X ishalogen selected from chlorine, bromine, fluorine and iodine, and Y isas defined above in this claim together with titanium tetrachloride andan excess of a tertiary amine and an inert liquid carrier to give acompound of the formula ##STR87## wherein Ar, Y, Z, X and R have thevalues given above in this claim and substantially separating it fromthe reaction mixture. Step 1, reacting a compound prepared in step A ora mixture of compounds of the formulas ##STR88## wherein Ar, Y, X, Z andR have the values as defined in step 1 with at least a stoichiometricamount of a strong non-nucleophilic alkali-metal base in stirrableadmixture with inert liquid carrier to give a compound of the formula##STR89## in said carrier of step 1 wherein; Ar, Y and Z are as definedabove in this claim, and R³ is an alkali-metal ion consisting of sodium,potassium or lithium or alk¹ --Q as defined in step A; Step 2,optionally when desired, reacting a compound as prepared in said carrierin step 1 wherein R³ is an alkali-metal ion with a proton source to givea compound of the formula ##STR90## in admixture with said liquidcarrier of step 1 wherein Ar, Z and Y are as defined above; Step 3, whendesired, reacting a compound as prepared in said carrier in step 1wherein R³ is an alkali-metal ion with a reagent having the formula

    halo--alk.sup.1 --Q

wherein Q is selected from hydrogen, --NR¹ R², --N═CH--OC₂ H₅ or##STR91## and R¹ and R² are selected from the group consisting ofloweralkyl, --C(O)--O--loweralkyl or R¹ and R² taken together with theadjacent nitrogen atom may form a heterocyclic residue selected from thegroup consisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl,4-morpholinyl, 1-piperazinyl and 4-substituted-piperazin-1-yl to give acompound of the formula ##STR92## in said carrier wherein Q has thestarting value of said reagent and Ar, Y, Z and alk¹ are as definedabove; Step 4, separating a compound prepared in step 1 other than acompound wherein R³ is a alkali-metal cation or a compound prepared insteps 2 or 3 by conventional means from said carrier and the reactionmixture to give a compound of the formula ##STR93## wherein Ar, Y, Z andR are as defined above, except R is not alkali-metal ion, and the acidaddition salts thereof; Step 5, when desired, reacting a compoundobtained in step 4 of the formula ##STR94## wherein Ar, Y, Z and alk¹are as defined above with a strong concentrated acid in protic solvent,preferably ethanol, to give a compound of the formula ##STR95## whereinAr, Y, Z and alk¹ are as defined above; Step 6, reacting a compoundprepared in step 5 with thionyl chloride to obtain a compound of theformula ##STR96## wherein Ar, Y, Z and alk¹ are as defined above; Step7, when desired, reacting a compound prepared in step 5 with a reagentof the formula

    WSO.sub.2 Cl

wherein W is loweralkyl, phenyl or tolyl to give a compound of theformula ##STR97## wherein Ar, Y, Z, alk¹ and W are as defined above;Step 8, when desired, reacting a compound prepared in steps 6 or 7 withammonia or a secondary or primary amine of the formula

    HNR.sup.1 R.sup.2

wherein R¹ and R² are as selected from hydrogen, loweralkyl, and --NR¹R² may be a heterocyclic radical to give a compound of the formula##STR98## wherein Ar, Y, Z, alk¹ and R¹, R² and NR¹ R² are as definedabove.